The abnormal accumulation of -amyloid (A) in the brain is believed to play a pivotal role in the etiology and pathogenesis of Alzheimer's disease (AD). A is produced continuously in the brain, but under normal circumstances its accumulation is prevented by its rapid catabolism. Compared to the breadth of knowledge concerning the enzymes and pathways involved in A production, relatively little research has been devoted to understanding A removal. Two lines of evidence indicate that endothelin-converting enzyme (ECE)-2 is an A degrading enzyme that regulates steady-state levels of the peptide in the brain, and that alterations in its activity potentially contribute to AD pathogenesis. First, we have shown that the steady-state levels of endogenous A are increased in the brains of mice deficient in ECE-2, similar to that observed in animals transgenic for AD-causing presenilin mutations. Second, ECE2 has been shown to be the single most down- regulated gene in AD brain by microarray analysis. Based on these data, our working hypothesis is that alterations in ECE-2 activity influence AD pathogenesis. We will test this hypothesis in three interrelated Aims that examine the ability of ECE-2 to directly degrade A in vitro and promote alterations in pathology in vivo in animal models. In addition, we will examine ECE-2 expression in our large series of brain tissue from autopsy- confirmed AD cases and age-matched controls and identify and analyze genetic variants in ECE2 to determine whether these correlate with alterations in gene expression and susceptibility to late-onset AD (LOAD).